Aspirin-like drugs may block pain independently of prostaglandin synthesis inhibition

Using flurbiprofen, a chiral anti-inflammatory and analgesic 2-arylpropionic acid derivative, the enantiomers of which are not converted to each other (less than 5%) in rats or man, we obtained evidence that prostaglandin synthesis inhibition is primarily mediating the anti-inflammatory activity but prostaglandin synthesis independent mechanisms contribute to the analgesic effects. Thus, the S-form inhibited prostaglandin synthesis, inflammation and nociception in rats. The R-form had much less effect on prostaglandin synthesis and did not affect inflammation. It did, however, block nociception in rats almost as potently as the S-form. S-flurbiprofen, in contrast to the R-form, was clearly ulcerogenic in the gastrointestinal mucosa. These results indicate additional molecular mechanisms of analgesia and suggest the use of R-arylpropionic acids as analgesics.     

Meclofenamate does not reduce chronic hypoxic pulmonary vasoconstriction.

There was no reduction in the pulmonary pressor response to hypoxia following inhibition of prostaglandin synthesis in rats exposed to chronic hypoxia. A fall in left ventricular weight suggested that systemic pressure may have been reduced after inhibition of prostaglandin synthesis in normoxic rats.     

Meclofenamate does not reduce chronic hypoxic pulmonary vasoconstriction

Summary There was no reduction in the pulmonary pressor response to hypoxia following inhibition of prostaglandin synthesis in rats exposed to chronic hypoxia. A fall in left ventricular weight suggested that systemic pressure may have been reduced after inhibition of prostaglandin synthesis in normoxic rats.This work was supported by NIH grant No. HL14985.     

Interference with histamine and imidazole acetic acid metabolism by salicylates: A possible contribution to salicylate analgesic activity?

Summary In man, rats and mice, the urinary excretion of the histamine andl-histidine metabolite, imidazole acetic acid, is increased and that of the conjugated metabolite, ribosylimidazole acetic acid, decreased by small doses of salicylates. In contrast to salicylates, other non-salicylate anti-inflammatory drugs, indomethacin, phenylbutazone, phenacetin and acetaminophen do not influence the excretion of the urinary metabolites of histamine andl-histidine. Since imidazole acetic acid is reported to have analgesic and narcotic activity, there is the inference that the analgesic properties of salicylate might be due in part to interference in imidazole acetic acid metabolism.     

Influence of flupirtine, a novel nonopioid analgesic agent on somatosensory evoked potentials in rats.

The effect of flupirtine, a novel nonopioid analgesic, on somatosensory evoked potentials (SEP) was investigated in anesthetized rats. Primary somatosensory potentials were evoked in the cerebral cortex by stimulation of the skin of the whiskery part of the face. Flupirtine injected i.p. dose-dependently prolonged the latency and reduced the amplitude of SEP with ID50-values of 5.4 mg/kg (2.6-9.3 mg/kg) and 7.9 mg/kg (3.9-13.8 mg/kg), respectively. This effect of flupirtine (10 mg/kg, i.p.) on the latency and the amplitude of SEP, did not change when naloxone (1 mg/kg, i.p.) was given before flupirtine. The results indicate that the analgesic flupirtine decreases the primary somatosensory evoked potential by diminishing the excitability of cortical neurons. Opioid mechanisms are not involved.     

Piroxicam-induced analgesia: Evidence for a central component which is not opioid mediated

Piroxicam is a nonsteroidal anti-inflammatory drug with a potent analgesic effect. In order to establish whether the analgesic action of Piroxicam has a central component, we studied the effect of the drug on the nociceptive orbicularis oculi reflexes evoked by electrical stimulation of the cornea and supraorbital nerve in healthy subjects. Piroxicam significantly suppressed the corneal reflex and R3 component of the blink reflex by 28% (p<0.05) and 50% (p<0.01), respectively. This effect was not reversed by the i.v. injection of naloxone. Beta-endorphin levels did not change. Piroxicam administration induces distinct inhibitory changes in nociceptive reflexes, which suggests that the analgesic action of the drug has a central component. The ineffectiveness of naloxone, and the lack of beta-endorphin changes, indicate that this central action is independent of the opioid system; other pain regulatory systems are probably involved.     

Piroxicam-induced analgesia: evidence for a central component which is not opioid mediated.

Piroxicam is a nonsteroidal anti-inflammatory drug with a potent analgesic effect. In order to establish whether the analgesic action of Piroxicam has a central component, we studied the effect of the drug on the nociceptive orbicularis oculi reflexes evoked by electrical stimulation of the cornea and supraorbital nerve in healthy subjects. Piroxicam significantly suppressed the corneal reflex and R3 component of the blink reflex by 28% (p < 0.05) and 50% (p < 0.01), respectively. This effect was not reversed by the i.v. injection of naloxone. Beta-endorphin levels did not change. Piroxicam administration induces distinct inhibitory changes in nociceptive reflexes, which suggests that the analgesic action of the drug has a central component. The ineffectiveness of naloxone, and the lack of beta-endorphin changes, indicate that this central action is independent of the opioid system; other pain regulatory systems are probably involved.     

Increased blood pressure in the SHR is not related to a deficit in renomedullary PGE2

Summary Synthesis of prostaglandin E₂ by renal medulla from SHR and WKY rats was compared during early postnatal development. Although arterial blood pressure was significantly higher in SHR as early as 6 weeks of age, no difference in renal medullary prostaglandin synthesis was observed.Supported in part by a grant from the michigan Heart Association and NIH grant AM-10913.     

Influence of flupirtine,a novel nonopioid analgesic agent on somatosensory evoked potentials in rats

The effect of flupirtine, a novel nonopioid analgesic, on somatosensory evoked potentials (SEP) was investigated in anesthetized rats. Primary somatosensory potentials were evoked in the cerebral cortex by stimulation of the skin of the whiskery part of the face. Flupirtine injected i.p. dose-dependently prolonged the latency and reduced the amplitude of SEP with ID₅₀-values of 5.4 mg/kg (2.6–9.3 mg/kg) and 7.9 mg/kg (3.9–13.8 mg/kg), respectively. This effect of flupirtine (10 mg/kg, i.p.) on the latency and the amplitude of SEP, did not change when naloxone (1 mg/kg, i.p.) was given before flupirtine. The results indicate that the analgesic flupirtine decreases the primary somatosensory evoked potential by diminishing the excitability of cortical neurons. Opioid mechanisms are not involved.     

Role of 1,25-dihydroxyvitamin D3 in the generation of the acute-phase response in rats with talc-induced granulomatosis

Subcutaneous injection of nonspecific irritants such as magnesium silicate (talc) provokes granulomatous inflammation in the rat. Part of the acute phase response (APR) in these animals is the loss of trabecular bone at sites distant from the site of inflammation. To assess the possible involvement of vitamin D in the bone loss, we studied the development of the acute phase response in vitamin D-deprived rats. The serum APR provoked by subcutaneous inflammation in rachitic rats consisted of hypozincemia, hypercupremia, increased, alkaline phosphatase activity and adrenocorticotropic hormone (ACTH) concentration, and was similar to that in control animals except for the absence of hypoferremia. Control rats with talc-induced subcutaneous inflammation also had splenomegaly and decreased total and mononuclear peripheral blood cell counts, while subcutaneous inflammation did not induce spleen changes in rachitic rats. Subcutaneous inflammation induced the loss of trabecular bone and decreased the osteoblastic cell count in tibial metaphyses in control animals. Rachitic rats had abundant osteoid on trabecular surfaces, and the number of osteoblasts and osteoclasts was comparable to that of the controls. Subcutaneous inflammation did not affect any of the bone parameters in rachitic rats. These results indicate that vitamin D plays an important role in the generation of the acute phase response during inflammation, particularly in the induction of spleen and bone cell changes. The discrepancy of the blood on one hand and bone and spleen indices of the APR on the other, indicate that there may be divergent pathways in the generation of the inflammatory response, some of which may be dependent on vitamin D.     

Interference with histamine and imidazole acetic acid metabolism by salicylates: a possible contribution to salicylate analgesic activity?

In man, rats and mice, the urinary excretion of the histamine and L-histidine metabolite, imidazole acetic acid, is increased and that of the conjugated metabolite, ribosylimidazole acetic acid, decreased by small doses of salicylates. In contrast to salicylates, other non-salicylate anti-inflammatory drugs, indomethacin, phenylbutazone, phenacetin and acetaminophen do not influence the excretion of the urinary metabolites of histamine and L-histidine. Since imidazole acetic acid is reported to have analgesic and narcotic activity, there is the inference that the analgesic properties of salicylate might be due in part to interference in imidazole acetic acid metabolism.     

Role of 5-hydroxytryptamine in prostaglandin E1-induced potentiation of hexobarbitone hypnosis in albino rats.

PGE1 potentiated, while diclofenac, a prostaglandin synthesis inhibitor, antagonized hexobarbitone hypnosis in rats. PGE1-induced potentiation of hexobarbitone sleep was inhibited by a 5HT synthesis inhibitor and by a 5HT receptor blocker, suggesting that this potentiation is 5HT mediated.     

Altered brain cyclic AMP-responses in rats reared in enriched or impoverished environments.

The accumulation of radioactive cyclic AMP elicited by various neurohormones has been examined in adenine-labeled telencephalon slices from rats raised in enriched or impoverished environments. Basal levels of cyclic AMP and responses of the brain slice cyclic AMP-generating systems to norepinephrine, isoproterenol and adenosine did not differ between the two group of rats, while responses to prostaglandin E1 were significantly greater with the impoverished group and responses to histamine appeared to be greater with the enriched group.     

Altered brain cyclic AMP-responses in rats reared in enriched or impoverished environments

Summary The accumulation of radioactive cyclic AMP elicited by various neurohormones has been examined in adenine-labeled telencephalon slices from rats raised in enriched or impoverished environments. Basal levels of cyclic AMP and responses of the brain slice cyclic AMP-generating systems to norepinephrine, isoproterenol and adenosine did not differe between the two group of rats, while responses to prostaglandin E₁ were significantly greater with the impoverished group and responses to histamine appeared to be greater with the enriched group.     

Suppression by the cyclohexanetrione Ro 31-0521 of retinoic acid-induced teratogenicity

The cyclohexanetrione Ro 31-0521, which stimulates prostaglandin synthesis, inhibited retinoic acid-induced cartilage degradation in vitro and suppressed the congenital forelimb malformations in rats treated with retinoic acid on day 13 of gestation in a dose-dependent manner.     

Inhibition of TSH-stimulated thyroid hormone release and potentiation of TRH-stimulated TSH release by indomethacin in perifusion systems of rat thyroids and pituitaries

Using indomethacin (Ind), a prostaglandin synthesis inhibitor, in vivo experiments in rats and in vitro experiments with perifusion systems of rat thyroids and pituitaries were conducted. After 35 days of intragastric infusion of Ind, serum TSH levels were markedly increased, the thyroid was swollen and, as a consequence, T3 and T4 levels were normal. The T3 release from perifused rat thyroids under continuous stimulation with 10 mU/ml TSH was inhibited significantly (p less than 0.01) by 1.0 X 10(-6) M Ind. On the other hand, the TSH release from perifused rat pituitaries under TRH stimulation was enhanced conspicuously by Ind. It was concluded that Ind decelerated thyroid hormone release from the thyroid and accelerated TSH release from the pituitary in perifusion systems.     

ACTH-induced hyperalgesia in rats.

The injection of ACTH 1--24 into the cerebral ventricles in rats markedly reduces the reaction time in the hot-plate test and the nociception threshold in the tail-stimulation test. Morphine antagonizes and naloxone potentiates this hyperalgesic effect of ACTH. It is proposed that ACTH peptides play a physiological role in nociception.     

Role of hsp70 in cytokine production

Interleukin-1 and tumor necrosis factor-alpha are potent, multifunctional cytokine mediators of inflammation and immune responses that are produced primarily by activated monocytes and macrophages. Three published papers by different groups have shown that heat shock and chemical stress with heavy metal salts or sulfhydryl reagents, all of which induce the expression of heat shock protein 70 (hsp70), concomitantly inhibit the production of these cytokines in human monocytes and mouse macrophages activated by lipopolysaccharide. These papers are reviewed and discussed in some detail. Other studies suggest that various anti-inflammatory drugs, including acetylsalicyclic acid, auranofin and dexamethasone, can also facilitate HSP expression in macrophages. However, while these studies are interesting, it is clear that not a great deal of work has been done and/or published in this area. Since many pharmaceutical companies are developing cytokine synthesis inhibitors as potential anti-inflammatory drugs, one aim of this article is to emphasize that understanding the molecular mechanism(s) that lead to increased HSP expression and decreased cytokine biosynthesis may assist in achieving this goal.     

ACTH-induced hyperalgesia in rats

Summary The injection of ACTH 1–24 into the cerebral ventricles in rats markedly reduces the reaction time in the hotplate test and the nociception threshold in the tail-stimulation test. Morphine antagonizes and naloxone potentiates this hyperalgesic effect of ACTH. It is proposed that ACTH peptides play a physiological role in nociception.     

Organoselenides as potential immunostimulants and inducers of interferon gamma and other cytokines in human peripheral blood leukocytes

Summary A number of organoselenium compounds have been described as anti-inflammatory, antioxidant, glutathione peroxidase-like agents and inhibitors of prostaglandin synthesis. Here we report that bis [2-(N-phenyl-carboxamido)]phenyl diselenide, 2-phenyl-1,2-benzisoselenazol-3(2H)-one (Ebselen) and related compounds are inducers of interferon gamma (IFN-) and tumor necrosis factor (TNF) in human peripheral blood leukocytes. The IFN and TNF response was rapid, occurring within 20 h, and high-up to 1000 and 2000 units ml^–1-and was clearly related to the dosage and the structure of the compounds. The action of the compounds and phytohemagglutinin was synergistic. The IFN gamma and TNF production was reduced after removing adherent cells. Although the mode of action of the compounds is not known, they appear to interact directly or indirectly with both adherent and non-adherent leukocytes, and stimulate the synthesis of a set of different cytokines including factors controlling the cell proliferation. Therefore, organoselenides may be regarded as the biological response modifiers.